Evaluation of Monier-Williams and Committee methods for bisulfite determination as used by the potato processing industry.
The Monier-Williams and the iodometric Committee methods were evaluated for the determination of bisulfite in potato products. Both methods showed critical problems in accuracy and precision at concentrations below 60 ppm. Sensitivity levels of 25 ppm are possible with the Monier-Williams method. However, accuracy problems reflected by the coefficients of variation (Monier-Williams, 47.4%; Committee, 78.2%) as well as variability in recoveries and blank values for both methods produce qualitative rather than quantitative analytical data at low SO2 concentrations.


Sexual Compulsivity Mediates the Association Between Childhood Sexual Abuse and Condom Use Resistance Among Men Who Have Sex with Men and Women.
Despite the continued prevalence of HIV and condoms' proven effectiveness in HIV prevention, many young men continue to engage in condom use resistance (CUR). Research shows that sexual compulsivity and childhood sexual abuse (CSA) victimization are risk factors for CUR. Given that sexual activity between men is the most common method through which HIV is transmitted, and that men who have sex with men and women (MSMW) are up to five times as likely to contract or transmit HIV as men who have sex with women only (MSWO), understanding the CUR behaviors of MSMW is uniquely important. Young, single men who had had sex with a woman in the past year (N = 623) completed questionnaires assessing their previous sexual experiences with men and women, history of CSA, sexual compulsivity, and CUR to determine how MSMW classification may moderate the associations between these variables. Results revealed full, moderated mediation, such that CSA was significantly associated with sexual compulsivity among MSMW, but not MSWO. Furthermore, sexual compulsivity was subsequently associated with CUR, in a model accounting for 5.35% of CUR variance. Such findings suggest that exposure to CSA may render MSMW especially susceptible to maladaptive, sexually compulsive desires and behaviors. As a result, MSMW may be more likely to disregard the inherent risks associated with condomless sexual activity and engage in CUR. Thus, intervention programs seeking to reduce the transmission of HIV and other STIs should prioritize targeting MSMW who experienced CSA to reduce sexual compulsivity and increase condom use.


Critical regulation of genes for tumor cell migration by AP-1.
The AP-1 transcription factor plays a critical role in regulating tumor cell proliferation and has been implicated in controlling a program of gene expression that mediates cell motility and invasion in vitro. We have utilized two dominant negative AP-1 constructs, TAM67 and aFos, each fused to GFP, to investigate the role of AP-1 complexes in an invasive, clinically derived human tumor cell line, HT-1080. As expected, high levels of both GFP-TAM67 and GFP-aFos arrested HT-1080 cells in the G1 phase of the cell cycle. Strikingly, at low levels GFP-aFos, but not GFP-TAM67, caused a change in colony morphology, impairment of directional motility in a monolayer wound healing assay, as well as inhibition of chemotaxis and haptotaxis. Microarray analysis identified a novel set of AP-1 target genes, including the tumor suppressor TSCL-1 and regulators of actin cytoskeletal dynamics, including the gelsolin-like actin capping protein CapG. The demonstration that AP-1 regulates the expression of genes involved in tumor cell motility and cytoskeletal dynamics in a clinically derived human tumor cell line identifies new pathways of control for tumor cell motility.


Psychosocial impact of Von Hippel-Lindau disease: levels and sources of distress.
Von Hippel-Lindau disease (VHL) is a hereditary tumor susceptibility syndrome, characterized by an increased risk of developing multiple benign and malignant tumors at various sites and ages with limited preventive options. This study evaluates the prevalence of distress among VHL family members and factors associated significantly with such distress. Forty-eight families with a VHL mutation were identified via the nine family cancer clinics in the Netherlands. In total, 171 family members (carriers, 50% at-risk, non-carriers) were approached, of whom 123 (72%) completed a self-report questionnaire. Approximately 40% of the VHL family members reported clinically relevant levels of distress, approaching 50% among the carriers and, possibly even more striking, 36% among the non-carriers. Having lost a first degree relative due to VHL during adolescence (OR 11.2; 95% CI 1.4-86.9) was related significantly to heightened levels of distress. Approximately, only one-third of those who reported heightened levels of distress had received professional psychosocial support. A substantial percentage of family members experience clinically relevant levels of distress. We would recommend the introduction of a procedure for screening for distress in this vulnerable population. Special attention should be paid to those individuals who have lost a close relative due to VHL during adolescence.


Detailed characterization of solute transport in a heterogeneous field soil.
There is a necessity for improved physical understanding of solute transport processes in heterogeneous soil systems. In situ nondestructive techniques like time domain reflectometry (TDR) and fiber optic miniprobes (FOMPs) permit the collection of unique measurements of solute transport processes in soils for the purposes of model development and validation. This study examined the application of TDR and FOMPs to measure solute transport at various points laterally and at two depths in a heterogeneous clay-loam soil. A miscible displacement experiment was performed at a constant irrigation flux to examine the applicability of these probes to field soils. In their first application to a field soil, the FOMPs were successfully calibrated and performed well in measuring solute breakthrough curves. Two flow regimes were identified in the soil profile, the first where lateral spreading of the solute occurred in the surface horizon, followed by convergence into preferential flow pathways in the second transport zone. The measured transport response was heterogeneous with at least two identifiable vertical flow phases. It was demonstrated using transfer function modeling and data from a corresponding laboratory study that the FOMPs were measuring the slower phase, while the TDR probes captured a composite of the fast and slow phases. The combination of these two techniques may be a means to separate solute transport phases in heterogeneous media and relate laboratory column results to field studies.


Properties of a series of tegumental membrane-bound phosphohydrolase activities of Schistosoma mansoni.
1. Incubation of Schistosoma mansoni for 5 min in a phosphate-buffered medium, pH 7.4, released tegumental material containing the following phosphohydrolase activities: alkaline phosphatase, 5'-nucleotidase, glycerol-2-phosphatase, glucose 6-phosphatase, phosphodiesterase and ATPase. 2. Maximum activity of these enzymes was measured at pH 9.5; however, the phosphodiesterase and ATPase activities were also appreciable at pH 7.0. 3. Solubilization of the released tegumental material in 1% Triton X-100 followed by gel filtration distinguished three peaks of enzyme activity: an ATPase (mol.wt. greater than 1000 000), a phosphodiesterase (mol.wt. 1 000 000) and an alkaline phosphomonoesterase with broad specificity (mol.wt. 232 000). 4. The ATPase activity was highly activated by 10 mM-Mg2+ or 1 mM-Ca2+ and was inhibited by chelating agents. Ouabain, Na+ and K+ had little effect on enzyme activity, whereas activity was increased by 50% in the presence of calmodulin. The phosphodiesterase activity was highest in the presence of 100 mM-Na+ or -K+, and 10 mM-Mg2+ or -Ca2+. Alkaline phosphatase activity was also stimulated by 100 mM-Na+ or -K+, and 10 mM-Mg2+; however Ca2+ inhibited at greater than 1 mM. 5. Surface iodination of parasites followed by detergent solubilization and gel filtration of the released tegumental membranes indicated that these enzymes were not accessible. A major surface component, apparent mol.wt. 80 000, was iodinated. 6. Rabbit anti-(mouse liver 5'-nucleotidase) antibodies did not inhibit the phosphohydrolase activities. However, an immunoglobulin G fraction from sera of mice chronically infected with S. mansoni partially inhibited alkaline phosphatase activity, but was without effect on the phosphodiesterase and ATPase activities. 7. The location of the enzymes in the double membrane of the tegument and their significance in host-parasite interactions is discussed.


Silicon decreases both uptake and root-to-shoot translocation of manganese in rice.
Silicon (Si) is known to alleviate manganese (Mn) toxicity in a number of plant species; however, the mechanisms responsible for this effect are poorly understood. Here, we investigated the interaction between Si and Mn in rice (Oryza sativa) by using a mutant defective in Si uptake. Silicon alleviated Mn toxicity in the wild-type (WT) rice, but not in the mutant exposed to high Mn. The Mn concentration in the shoots was decreased, but that in the roots was increased by Si in the WT. In contrast, the Mn concentration in the roots and shoots was unaffected by Si in the mutant. Furthermore, Si supply resulted in an increased Mn in the root cell sap, decreased Mn in the xylem sap in the WT, but these effects of Si were not observed in the mutant. A short-term labelling experiment with (54)Mn showed that the uptake of Mn was similar between plants with and without Si and between WT and the mutant. However, Si decreased root-to-shoot translocation of Mn in the WT, but not in the mutant. The expression of a Mn transporter gene for uptake, OsNramp5, was unaffected by a short exposure (<1 d) to Si, but down-regulated by relatively long-term exposure to Si in WT. In contrast, the expression of OsNramp5 was unaffected by Si in the mutant. These results indicated that Si-decreased Mn accumulation results from both Si-decreased root-to-shoot translocation of Mn, probably by the formation of Mn-Si complex in root cells, and uptake by down-regulating Mn transporter gene.


Conformational changes during nucleotide selection by Sulfolobus solfataricus DNA polymerase Dpo4.
The mechanism of nucleotide selection by Y-family DNA polymerases has been the subject of intense study, but significant structural contacts and/or conformational changes that relate to polymerase fidelity have been difficult to identify. Here we report on the conformational dynamics of a model Y-family polymerase Dpo4 from Sulfolobus solfataricus. Hydrogen-deuterium exchange in tandem with mass spectrometry was used to monitor changes in Dpo4 structure as a function of time and the presence or absence of specific substrates and ligands. Analysis of the data revealed previously unrecognized structural changes that accompany steps in the catalytic cycle leading up to phosphoryl transfer. For example, the solvent accessibility of the alphaB-loop-alphaC region in the finger domain decreased in the presence of all four dNTP insertion events, but the rate of deuterium exchange, an indicator of conformational flexibility, only decreased during an accurate insertion event. Of particular note is a change in the region surrounding the H-helix of the thumb domain. Upon binding DNA and Mg2+, the H-helix showed a decrease in solvent accessibility and flexibility that was relaxed only upon addition of dCTP, which forms a Watson-Crick base pair with template dG and not during mispairing events. The current study expands upon a previous report from our group that used a fluorescent probe located near the thumb domain to measure the kinetic properties of Dpo4 conformational changes. We now present a model for nucleotide selection by Dpo4 that arises from a synthesis of both structural and kinetic data.


Genome-wide brain DNA methylation analysis suggests epigenetic reprogramming in Parkinson disease.
Given the known strong relationship of DNA methylation with environmental exposure, we investigated whether brain regions affected in Parkinson disease (PD) were differentially methylated between PD cases and controls. DNA chip arrays were used to perform a genome-wide screen of DNA methylation on the dorsal motor nucleus of the vagus (DMV), substantia nigra (SN), and cingulate gyrus (CG) of pathologically confirmed PD cases and controls selected using the criteria of Beecham et al. Analysis examined differentially methylated regions (DMRs) between cases and controls for each brain area. RNA sequencing and pathway analysis were also performed for each brain area. Thirty-eight PD cases and 41 controls were included in the analysis. Methylation studies revealed 234 significant DMR in the DMV, 44 in the SN, and 141 in the CG between cases and controls (Sidak p < 0.05). Pathway analysis of these genes showed significant enrichment for the Wnt signaling pathway (FDR < 0.01). Our data suggest that significant DNA methylation changes exist between cases and controls in PD, especially in the DMV, one of the areas affected earliest in PD. The etiology of these methylation changes is not yet known, but the predominance of methylation changes occurring in the DMV supports the hypothesis that vagus nerve function, perhaps involving the gastrointestinal system, is important in PD pathogenesis. These data also give independent support that genes involved in Wnt signaling are a likely factor in the neurodegenerative processes of PD.


Increased local failure for patients with intermediate-risk rhabdomyosarcoma on ARST0531: A report from the Children's Oncology Group.
The objective of this study was to evaluate local control for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group (COG) protocol ARST0531. This study analyzed 424 patients with intermediate-risk RMS. Patients were randomized to chemotherapy with either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC alternating with vincristine and irinotecan. With the goal of improving local control, radiation therapy (RT) was delivered early at week 4 and was concurrent with irinotecan in the experimental arm. Individualized local control plans for children 24 months old or younger were allowed. Local failure on ARST0531 was compared with local failure on the preceding COG intermediate-risk study, D9803. For patients with group I/II alveolar RMS (n = 55), the 5-year cumulative incidence of local failure was 13.4%; for group III alveolar RMS (n = 141), it was 20.2%; and for group III embryonal RMS (n = 228), it was 27.9% (P = .03). Among patients with group III disease, local failure did not differ by histology, site, nodal status, RT modality, or treatment arm. Local failure was worse for a tumor size >5 cm (32.3% vs 16.7%; P = .001). Among patients with group III embryonal RMS, local failure was higher on ARST0531 than D9803 (27.9% vs 19.4%; P = .03). After the exclusion of patients 24 months old or younger or patients who did not receive radiation, local failure remained significantly increased on ARST0531 (P = .02). After adjustments for clinical prognostic factors, event-free survival and overall survival were worse on ARST0531 (P = .004 and P = .05, respectively). Despite interventions designed to enhance local control, local control was inferior on ARST0531 in comparison with D9803. The reason for this is unclear, but it could be the reduced cyclophosphamide dose on ARST0531.


Determinants of endothelial function in human immunodeficiency virus infection: a complex interplay among therapy, disease, and host factors.
In the era of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV) infection has become a chronic disease in which patients may develop significant metabolic complications and risk factors for cardiovascular disease (CVD), including insulin resistance, visceral fat deposition, and increases in atherogenic cholesterol and triglyceride levels. Epidemiologic studies have found that persons infected with HIV are likely to be at higher risk for premature CVD compared with the general population, and clinical studies examining endothelial function in HIV-infected cohorts have supported such conclusions. The mechanisms underlying the regulation of endothelial function in HIV-infected persons appear to be multifactorial, including direct effects of HIV on the endothelium, indirect effects of HIV on lipids and inflammatory cytokines, HAART-related effects, and traditional/host factors. Better understanding of these processes can lead to improved strategies for the long-term management of HIV infection.


Cardioprotection in pigs by exogenous norepinephrine but not by cerebral ischemia-induced release of endogenous norepinephrine.
Endogenous norepinephrine release induced by cerebral ischemia may lead to small areas of necrosis in normal hearts. Conversely, norepinephrine may be one of the mediators that limit myocardial infarct size by ischemic preconditioning. Because brief ischemia in kidneys or skeletal muscle limits infarct size produced by coronary artery occlusion, we investigated whether cardiac norepinephrine release during transient cerebral ischemia also elicits remote myocardial preconditioning. Forty-one crossbred pigs of either sex were assigned to 1 of 7 experimental groups, of which in 6 groups myocardial infarct size was determined after a 60-minute coronary occlusion and 120 minutes of reperfusion. One group served as control (no pretreatment), while the other groups were pretreated with either cerebral ischemia or an intracoronary infusion of norepinephrine. In 10 anesthetized control pigs, infarct size was 84+/-3% (mean+/-SEM) of the area at risk after a 60-minute coronary occlusion and 120 minutes of reperfusion. Intracoronary infusion of 0.03 nmol/kg. min(-)(1) norepinephrine for 10 minutes before coronary occlusion did not affect infarct size (80+/-3%; n=6), whereas infusion of 0.12 nmol/kg. min(-)(1) limited infarct size (65+/-2%; n=7; P:<0.05). Neither 10-minute (n=5) nor 30-minute (n=6) cerebral ischemia produced by elevation of intracranial pressure before coronary occlusion affected infarct size (83+/-4% and 82+/-3%, respectively). Myocardial interstitial norepinephrine levels tripled during cerebral ischemia and during low-dose norepinephrine but increased 10-fold during high-dose norepinephrine. Norepinephrine levels increased progressively up to 500-fold in the area at risk during the 60-minute coronary occlusion, independent of the pretreatment, while norepinephrine levels remained unchanged in adjacent nonischemic myocardium and arterial plasma. Cerebral ischemia preceding a coronary occlusion did not modify infarct size, which is likely related to the modest increase in myocardial norepinephrine levels during cerebral ischemia. The infarct size limitation by high-dose exogenous norepinephrine is not associated with blunting of the ischemia-induced increase in myocardial interstitial norepinephrine levels.


[Effect of chronic hypoxia on endothelium-dependent relaxation and the content of cGMP in rat pulmonary artery].
This experiment was designed to investigate whether chronic hypoxia affect rat pulmonary artery (PA) endothelium-dependent relaxation and the content of cGMP in PA. Both ACh and ATP could induce endothelium-dependent relaxation of PA, not prevented by indomethacin, but completely abolished by methylene blue. These results indicated that vasodilatation of PA induced by both ACh and ATP is mediated by EDRF (endothelium-derived relaxing factor). Chronic hypoxia significantly depressed PA endothelium-dependent relaxation. The percent relaxation of IPPA and EPPA by 10(-6) mol/L ACh was 61.3% and 59.2% of those in control, and the percent relaxation of IPPA and EPPA by 1.8 x 10(-5) mol/L ATP was 64.9% and 55.3% respectively of the control. Chronic hypoxia also depressed SNP-induced endothelium-independent relaxation. Chronic hypoxia significantly decreased the content of cGMP in PA. The basic level of cGMP was 51.9 +/- 5.7 (n = 14) in hypoxia group and 84.9 +/- 9.7 (n = 14) pmol/g wet wt. in control group (P less than 0.01). After treatment of PA with ACh (10(-7) mol/L), the content of cGMP was 91.4 +/- 7.3 (n = 5) pmol/g wet wt. in hypoxic group and 240.8 +/- 30.6 (n = 5) pmol/g wet wt. in control group (P less than 0.01). Our data suggest that chronic hypoxia might depress rat pulmonary artery endothelium-dependent relaxation through the inhibition of soluble guanylate cyclase in vascular smooth muscle cells.


Effect of gender on outcome of out of hospital cardiac arrest in the Resuscitation Outcomes Consortium.
This study examined the relationship between gender and outcomes of non-traumatic out-of-hospital cardiac arrest (OHCA). All eligible, consecutive, non-traumatic Emergency Medical Services (EMS) treated OHCA patients in the Resuscitation Outcomes Consortium between December 2005 and May 2007. Patient age was analyzed as a continuous variable and stratified in two age cohorts: 15-45 and >55 years of age (yoa). Unadjusted and adjusted (based on Utstein characteristics) chi square tests and logistic regression models were employed to examine the relationship between gender, age, and survival outcomes. This study enrolled 14,690 patients: of which 36.4% were women with a mean age of 68.3 and 63.6% of them men with a mean age of 64.2. Women survived to hospital discharge less often than men (6.4% vs. 9.1%, p<0.001); the unadjusted OR was 0.69, 95%CI: 0.60, 0.77 whereas when adjusted for all Utstein predictors the difference was not significant (OR: 1.16, 95%CI: 0.98, 1.36, p=0.07). The adjusted survival rate for younger women (15-45 yoa) was 11.1% vs. 9.8% for younger men (OR: 1.66, 95%CI: 1.04, 2.64, p=0.03) but no difference in discharge rates was observed in the >55 cohort (OR: 0.94, 95%CI: 0.78, 1.15, p=0.57). Women who suffer OHCAs have lower rates of survival and have unfavourable Utstein predictors. When survival is adjusted for these predictors survival is similar between men and women except in younger women suggesting that age modifies the association of gender and survival from OHCA; a result that supports a protective hormonal effect among premenopausal women.


Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer.
This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors. Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug. Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042). COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.


Initial laparoscopic appendectomy versus initial nonoperative management and interval appendectomy for perforated appendicitis with abscess: a prospective, randomized trial.
Perforated appendicitis is a common condition in children, which, in a small number of patients, may be complicated by a well-formed abscess. Initial nonoperative management with percutaneous drainage/aspiration of the abscess followed by intravenous antibiotics usually allows for an uneventful interval appendectomy. Although this strategy has become well accepted, there are no published data comparing initial nonoperative management (drainage/interval appendectomy) to appendectomy upon presentation with an abscess. Therefore, we conducted a randomized trial comparing these 2 management strategies. After internal review board approval (#06 11-164), children who presented with a well-defined abdominal abscess by computed tomographic imaging were randomized on admission to laparoscopic appendectomy or intravenous antibiotics with percutaneous drainage of the abscess (when possible), followed by interval laparoscopic appendectomy approximately 10 weeks later. This was a pilot study with a sample size of 40, which was based on our recent volume of patients presenting with appendicitis and abscess. On presentation, there were no differences between the 2 groups regarding age, weight, body mass index, sex distribution, temperature, leukocyte count, number of abscesses, or greatest 2-dimensional area of abscess in the axial view. Regarding outcomes, there were no differences in length of total hospitalization, recurrent abscess rates, or overall charges. There was a trend toward a longer operating time in patients undergoing initial appendectomy (61 minutes versus 42 minutes mean, P = .06). Although initial laparoscopic appendectomy trends toward a requiring longer operative time, there seems to be no advantages between these strategies in terms of total hospitalization, recurrent abscess rate, or total charges.


Evaluation of Potential Transfer of the Pathogen Saprolegnia parasitica between Farmed Salmonids and Wild Fish.
Saprolegnia infections are among the main parasitic diseases affecting farmed salmonids. The distribution and potential transfer of Saprolegnia spp. between farms and the natural environment has been scarcely investigated. Therefore, this work aimed to study the diversity and abundance of oomycete species in salmonid farms, tributary water, and effluent water systems. Four trout farms in Italy and two Atlantic salmon farms in Scotland were considered. In Italian farms, 532 isolates of oomycetes were obtained from fish and water, at upstream, inside, and downstream the farms. In Scottish farms, 201 oomycetes isolates were obtained from water outside the farm and from fish and water inside the farming units. Isolates were identified to the species level through amplification and sequencing of the ITS rDNA region. In Italy, S. parasitica was significantly more present in farmed than in wild fish, while in water it was more frequently isolated from the wild, particularly in effluent systems, not associated with more frequent isolation of S. parasitica in wild fish downstream the farm. In Scotland, S. parasitica was the most prevalent species isolated from fish, while isolates from water were mostly Pythium spp. with few S. parasitica isolates from upstream and downstream the farms.


HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy.
Hodgkin lymphoma (HL) incidence with HIV infection may have increased with the introduction of combination antiretroviral therapy (cART), suggesting that immune reconstitution may contribute to some cases. We evaluated HL risk with cART during the first months of treatment. With 187 HL cases among 64 368 HIV patients in France, relative rates (RRs) and 95% confidence intervals (CIs) of HL were estimated using Poisson models for duration of cART, CD4 count, and HIV load, with and without adjustment for demographic/clinical covariates. HL risk was unrelated to cART use overall, but it was related to time intervals after cART initiation (P = .006). Risk was especially and significantly elevated in months 1-3 on cART (RR 2.95, CI 1.64-5.31), lower in months 4-6 (RR 1.63), and null with longer use (RR 1.00). CD4 count was strongly associated with HL risk (P < 10⁻⁶), with the highest HL incidence at 50-99 CD4 cells/mm³. With adjustment for CD4 count and covariates, HL risk was elevated, but not significantly (RR 1.42), in months 1-3 on cART. HIV load had no added effect. HL risk increased significantly soon after cART initiation, which was largely explained by the CD4 count. Further studies of HIV-associated HL are needed.


Next-Generation Sequencing of Plasmodium vivax Patient Samples Shows Evidence of Direct Evolution in Drug-Resistance Genes.
Understanding the mechanisms of drug resistance in Plasmodium vivax, the parasite that causes the most widespread form of human malaria, is complicated by the lack of a suitable long-term cell culture system for this parasite. In contrast to P. falciparum, which can be more readily manipulated in the laboratory, insights about parasite biology need to be inferred from human studies. Here we analyze the genomes of parasites within 10 human P. vivax infections from the Peruvian Amazon. Using next-generation sequencing we show that some P. vivax infections analyzed from the region are likely polyclonal. Despite their polyclonality we observe limited parasite genetic diversity by showing that three or fewer haplotypes comprise 94% of the examined genomes, suggesting the recent introduction of parasites into this geographic region. In contrast we find more than three haplotypes in putative drug-resistance genes, including the gene encoding dihydrofolate reductase-thymidylate synthase and the P. vivax multidrug resistance associated transporter, suggesting that resistance mutations have arisen independently. Additionally, several drug-resistance genes are located in genomic regions with evidence of increased copy number. Our data suggest that whole genome sequencing of malaria parasites from patients may provide more insight about the evolution of drug resistance than genetic linkage or association studies, especially in geographical regions with limited parasite genetic diversity.


Incorporating a brief intervention for personalised cancer risk assessment to promote behaviour change into primary care: a multi-methods pilot study.
Approximately 40% of cancers could be prevented if people lived healthier lifestyles. We have developed a theory-based brief intervention to share personalised cancer risk information and promote behaviour change within primary care. This study aimed to assess the feasibility and acceptability of incorporating this intervention into primary care consultations. Patients eligible for an NHS Health Check or annual chronic disease review at five general practices were invited to participate in a non-randomised pilot study. In addition to the NHS Health Check or chronic disease review, those receiving the intervention were provided with their estimated risk of developing the most common preventable cancers alongside tailored behaviour change advice. Patients completed online questionnaires at baseline, immediately post-consultation and at 3-month follow-up. Consultations were audio/video recorded. Patients (n = 12) and healthcare professionals (HCPs) (n = 7) participated in post-intervention qualitative interviews that were analysed using thematic analysis. 62 patients took part. Thirty-four attended for an NHS Health Check plus the intervention; 7 for a standard NHS Health Check; 16 for a chronic disease review plus the intervention; and 5 for a standard chronic disease review. The mean time for delivery of the intervention was 9.6 min (SD 3) within NHS Health Checks and 9 min (SD 4) within chronic disease reviews. Fidelity of delivery of the intervention was high. Data from the questionnaires demonstrates potential improvements in health-related behaviours following the intervention. Patients receiving the intervention found the cancer risk information and lifestyle advice understandable, useful and motivating. HCPs felt that the intervention fitted well within NHS Health Checks and facilitated conversations around behaviour change. Integrating the intervention within chronic disease reviews was more challenging. Incorporating a risk-based intervention to promote behaviour change for cancer prevention into primary care consultations is feasible and acceptable to both patients and HCPs. A randomised trial is now needed to assess the effect on health behaviours. When designing that trial, and other prevention activities within primary care, it is necessary to consider challenges around patient recruitment, the HCP contact time needed for delivery of interventions, and how best to integrate discussions about disease risk within routine care.


Expression profiles of genes regulating dairy cow fertility: recent findings, ongoing activities and future possibilities.
Subfertility has negative effects for dairy farm profitability, animal welfare and sustainability of animal production. Increasing herd sizes and economic pressures restrict the amount of time that farmers can spend on counteractive management. Genetic improvement will become increasingly important to restore reproductive performance. Complementary to traditional breeding value estimation procedures, genomic selection based on genome-wide information will become more widely applied. Functional genomics, including transcriptomics (gene expression profiling), produces the information to understand the consequences of selection as it helps to unravel physiological mechanisms underlying female fertility traits. Insight into the latter is needed to develop new effective management strategies to combat subfertility. Here, the importance of functional genomics for dairy cow reproduction so far and in the near future is evaluated. Recent gene profiling studies in the field of dairy cow fertility are reviewed and new data are presented on genes that are expressed in the brains of dairy cows and that are involved in dairy cow oestrus (behaviour). Fast-developing new research areas in the field of functional genomics, such as epigenetics, RNA interference, variable copy numbers and nutrigenomics, are discussed including their promising future value for dairy cow fertility.


Speckle noise reduction of medical ultrasound images in complex wavelet domain using mixture priors.
Speckle noise is an inherent nature of ultrasound images, which may have negative effect on image interpretation and diagnostic tasks. In this paper, we propose several multiscale nonlinear thresholding methods for ultrasound speckle suppression. The wavelet coefficients of the logarithm of image are modeled as the sum of a noise-free component plus an independent noise. Assuming that the noise-free component has some local mixture distribution (MD), and the noise is either Gaussian or Rayleigh, we derive the minimum mean squared error (MMSE) and the averaged maximum a posteriori (AMAP) estimators for noise reduction. We use Gaussian and Laplacian MD for each noise-free wavelet coefficient to characterize their heavy-tailed property. Since we estimate the parameters of the MD using the expectation maximization (EM) algorithm and local neighbors, the proposed MD incorporates some information about the intrascale dependency of the wavelet coefficients. To evaluate our spatially adaptive despeckling methods, we use both real medical ultrasound and synthetically introduced speckle images for speckle suppression. The simulation results show that our method outperforms several recently and the state-of-the-art techniques qualitatively and quantitatively.


Incorporation of fasting therapy in an integrative medicine ward: evaluation of outcome, safety, and effects on lifestyle adherence in a large prospective cohort study.
The aim of this study was to implement fasting therapy in an inpatient integrative medicine ward and to evaluate safety, acceptance, and effects on health-related outcomes and lifestyle adherence. This was a prospective observational study with consecutive inpatients over 3 [corrected] years. Inclusion and exclusion criteria for fasting therapy were checked by treating physicians and recommendations given. After receiving full information patients decided whether they would participate in fasting. Outcomes were assessed on admission, at discharge, and 3 and 6 months after discharge. The study took place in an integrative medicine department of an academic teaching hospital. Subjects were newly admitted inpatients with chronic internal diseases and chronic pain syndromes, with lengths of hospital stay of >3 days. All patients received intensive integrative treatments including Mind/Body Medicine, acupuncture, nutritional/lifestyle education, and hydrotherapy. Fasting patients participated in a 7-day juice fast (intake <350 kcal/day) with accompanying bowel cleansing, 2 prefasting relief days, and 3 days with stepwise reintroduction of food. Outcomes were assessed based on rate of participation in fasting, severity of main complaint, quality of life (QOL, MOS 36-Item Short-Form Health Survey), safety, lifestyle adherence to recommendations given (relaxation, diet, exercise). Of 2121 patients with complete discharge questionnaires, 952 patients participated in fasting, 873 had a normocaloric vegetarian diet, and 296 patients had other diets and were excluded. Response rates were 71% and 56% at 3- and 6-month follow-up. The main disease-related complaint at discharge was significantly greater improved in fasters versus nonfasters (p < 0.01). Patient QOL increased significantly and comparably from baseline to discharge in both groups. Fasting was well tolerated and no serious fasting-related adverse effects were reported. In all, 743 (78%) of fasting patients reported improvement of their health through fasting. Descriptors of lifestyle adherence showed higher levels of related activities in the 3 and 6 months of follow-up. Fasting can safely and successfully be implemented in an inpatient integrative medicine concept and is perceived as a health-promoting method by the majority of patients. Potential effects on disease-related complaints and lifestyle adherence should be further evaluated in randomized trials.


PCA2GO: a new multivariate statistics based method to identify highly expressed GO-Terms.
Several tools have been developed to explore and search Gene Ontology (GO) databases allowing efficient GO enrichment analysis and GO tree visualization. Nevertheless, identification of highly specific GO-terms in complex data sets is relatively complicated and the display of GO term assignments and GO enrichment analysis by simple tables or pie charts is not optimal. Valuable information such as the hierarchical position of a single GO term within the GO tree (topological ordering), or enrichment within a complex set of biological experiments is not displayed. Pie charts based on GO tree levels are, themselves, one-dimensional graphs, which cannot properly or efficiently represent the hierarchical specificity for the biological system being studied. Here we present a new method, which we name PCA2GO, capable of GO analysis using complex multidimensional experimental settings. We employed principal component analysis (PCA) and developed a new score, which takes into account the relative frequency of certain GO terms and their specificity (hierarchical position) within the GO graph. We evaluated the correlation between our representation score R and a standard measure of enrichment, namely p-values to convey the versatility of our approach to other methods and point out differences between our method and commonly used enrichment analyses. Although p values and the R score formally measure different quantities they should be correlated, because relative frequencies of GO terms occurrences within a dataset are an indirect measure of protein numbers related to this term. Therefore they are also related to enrichment. We showed that our score enables us to identify more specific GO-terms i.e. those positioned further down the GO-graph than other common tools used for this purpose. PCA2GO allows visualization and detection of multidimensional dependencies both within the acyclic graph (GO tree) and the experimental settings. Our method is intended for the analysis of several experimental sets, not for one set, like standard enrichment tools. To demonstrate the usefulness of our approach we performed a PCA2GO analysis of a fractionated cardiomyocyte protein dataset, which was identified by enhanced liquid chromatography-mass spectrometry (GeLC-MS). The analysis enabled us to detect distinct groups of proteins, which accurately reflect properties of biochemical cell fractions. We conclude that PCA2GO is an alternative efficient GO analysis tool with unique features for detection and visualization of multidimensional dependencies within the dataset under study. PCA2GO reveals strongly correlated GO terms within the experimental setting (in this case different fractions) by PCA group formation and improves detection of more specific GO terms within experiment dependent GO term groups than standard p value calculations.


Biochemical changes in Pinus pinea seeds during storing.
The changes in the germination-rate, the contents in germination-inhibitors and the biochemical differences in soluble proteins and nucleic acids in freshly harvested Pinus pinea seeds stored for various periods of time, up to 24 months, and at two different temperatures (room temperature and 4 degrees C), have been investigated. The present results show that the maturation or after-ripening process of this type of seeds might be induced during the first 6 and 12 months of storage. However, seeds stored for longer periods of time might also be thought to enter into the primary phases of the ageing process where early alterations occur, including the loss of germination-rate and germination-inhibitor contents in the seed coat, together with an incapacity for the seeds to increase their protein and nucleic acid levels during the germination process.


Keratinocyte growth factor ameliorates radiation- and bleomycin-induced lung injury and mortality.
Keratinocyte growth factor (KGF) is a growth factor for type II pneumocytes. Type II pneumocyte hyperplasia, a common reaction to lung injury, has been postulated to play an important role in lung repair. The potential protective effect of KGF was therefore studied in rat models of radiation- and bleomycin-induced lung injury. Intratracheal instillation of KGF (5 mg/kg) 72 and 48 hours before 18 Gy of bilateral thoracic irradiation did not significantly improve survival, although histology showed less pneumonitis and fibrosis in KGF-pretreated as compared with control-irradiated rats. Intratracheal pretreatment with KGF in rats receiving intratracheal bleomycin (2.5 U) improved survival at 3 weeks to 100% (20/20 rats) from 40% (8/20 rats) in controls. All KGF-pretreated rats receiving bleomycin were well at 3 weeks and without histological evidence of pulmonary fibrosis whereas the 8 surviving control rats exhibited severe respiratory distress. Finally, in the most lethal challenge to the lung, rats pretreated with intratracheal KGF or saline were challenged with a combination of bleomycin (1.5 U) and bilateral thoracic irradiation (18 Gy). KGF-pretreated rats did not begin to die or show signs of respiratory distress until 7 weeks, whereas all saline-pretreated control rats receiving radiation and bleomycin died within approximately 4 weeks with severe respiratory distress and weight loss. In conclusion, radiation- and bleomycin-induced pulmonary injury and respiratory death are ameliorated by KGF pretreatment, suggesting a protective role for KGF-induced type II pneumocyte proliferation in lung injury.


Macrophage Elastase Induces TRAIL-mediated Tumor Cell Death through Its Carboxy-Terminal Domain.
Macrophage elastase (matrix metalloproteinase [MMP]-12) is a potent protease that contributes to the lung destruction that accompanies cigarette smoking; it simultaneously inhibits lung tumor angiogenesis and metastasis by catalyzing the formation of antiangiogenic peptides. Recent studies have revealed novel nonproteolytic functions of MMP12, including antimicrobial activity through a peptide within its C-terminal domain (CTD). To determine whether the MMP12 CTD contributes to its antitumor activity in lung cancer. We used recombinant MMP12 peptide fragments, including its catalytic domain, CTD, and a 20 amino acid peptide within the CTD (SR20), in an in vitro system to delineate their effects on non-small cell lung cancer cell proliferation and apoptosis. We translated our findings to two murine models of lung cancer, including orthotopic human xenograft and KrasLSL/G12D mouse models of lung cancer. We show that SR20 triggers tumor apoptosis by up-regulation of gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 4, sensitizing cells to an autocrine loop of TRAIL-mediated cell death. We then demonstrate the therapeutic efficacy of SR20 against two murine models of lung cancer. The MMP12 CTD initiates TRAIL-mediated tumor cell death through its conserved SR20 peptide.


Cryptosporidiosis in a pup.
Cryptosporidiosis is a coccidian parasitism which has been implicated as a cause of diarrhea in man and a variety of animals. Cryptosporidiosis was diagnosed in a one-week-old pup which had a history of acute diarrhea. Organisms, 2 to 3 mm in diameter, covered the microvillous border of intestinal epithelium. Ultrastructurally, the cryptosporidia had one or more nuclei with prominent nucleoli and abundant cytoplasmic endoplasmic reticulum. Cryptosporidia may have played a role in the enteritis seen in this pup but further studies are needed to establish its pathogenicity.


Rehabilitation of Atrophic Mandible with Ultrashort Implants Combined with Photobiomodulation Therapy: A Split-Mouth Design Study.
Atrophic edentulous mandible is a challenging clinical condition. Studies assessing the use of ultrashort implants to support overdentures are scarce; the optimum photobiomodulation (PBM) dose for enhancing osseointegration is yet unknown. This study aimed to evaluate and compare mandibular overdentures assisted by two versus four ultrashort implants with adjunctive PBM therapy using two doses. A total of 36 implants were placed in 12 edentulous male participants and they were randomly allocated to Group I (mandibular overdentures assisted by two ultrashort implants) or Group II (by four ultrashort implants). Fully guided implant placement was performed, and then a split-mouth design was implemented. The participants received PBM by diode laser (660 nm). Dose A (3.75 J/cm2) and Dose B (7.5 J/cm2) were applied to the right and left implant (s), respectively. Implant stability, peri-implant probing depth (PIPD), and modified gingival index (MGI) were evaluated at baseline, and at 6 and 12 months after loading. After 12 months, the implant stability values were significantly higher in Group II compared with Group I (P < 0.001). A significant difference was observed in between the PIPDs of both groups (Group I: 2.35 ± 0.54 mm; Group II: 1.69 ± 0.35 mm;P= 0.001). The mean MGI values were low for both groups (Group I: 0.75 ± 0.58; Group II: 0.51 ± 0.41). Mandibular overdentures supported by four ultrashort implants had a more favorable clinical outcome, while PBM doses A and B were comparable in all evaluated parameters. ClinicalTrials.gov Identifier: NCT03540316.


Profile of participants and genotype distributions of 108 polymorphisms in a cross-sectional study of associations of genotypes with lifestyle and clinical factors: a project in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study.
Most diseases are thought to arise from interactions between environmental factors and the host genotype. To detect gene-environment interactions in the development of lifestyle-related diseases, and especially cancer, the Japan Multi-institutional Collaborative Cohort (J-MICC) Study was launched in 2005. We initiated a cross-sectional study to examine associations of genotypes with lifestyle and clinical factors, as assessed by questionnaires and medical examinations. The 4519 subjects were selected from among participants in the J-MICC Study in 10 areas throughout Japan. In total, 108 polymorphisms were chosen and genotyped using the Invader assay. The study group comprised 2124 men and 2395 women with a mean age of 55.8 ± 8.9 years (range, 35-69 years) at baseline. Among the 108 polymorphisms examined, 4 were not polymorphic in our study population. Among the remaining 104 polymorphisms, most variations were common (minor allele frequency ≥0.05 for 96 polymorphisms). The allele frequencies in this population were comparable with those in the HapMap-JPT data set for 45 Japanese from Tokyo. Only 5 of 88 polymorphisms showed allele-frequency differences greater than 0.1. Of the 108 polymorphisms, 32 showed a highly significant difference in minor allele frequency among the study areas (P < 0.001). This comprehensive data collection on lifestyle and clinical factors will be useful for elucidating gene-environment interactions. In addition, it is likely to be an informative reference tool, as free access to genotype data for a large Japanese population is not readily available.


Pd-catalyzed access to mono- and di-fluoroallylic amines from primary anilines.
The Pd-catalyzed highly selective synthesis of mono- and di-2-fluoroallylic amines from gem-difluorocyclopropanes and ubiquitous unprotected primary anilines is herein described. Initial kinetic investigations suggest a first order in the gem-difluorocyclopropane substrate, as well as a circa zeroth order in the aniline coupling partner. The newly produced fluoroallylic motifs should find important applications in synthetic as well as medicinal chemistry and stimulate the further development of coupling methods based on strained cyclic building blocks.


Long-Term Survival Is Superior in Patients With Pulsatile Pulmonary Flow After the Björk Procedure.
Background: This study aims to evaluate clinical outcomes and hemodynamic variables late after the Björk procedure, regarding the pulmonary flow pattern. Methods: Patients who survived more than 15 years after the Björk procedure were included and then divided into two groups according to their pulmonary flow pattern by pulsed-wave Doppler assessment of echocardiography: patients with pulsatile systolic pulmonary flow (Group P) and those without (Group N). Results: A total of 43 patients were identified, of whom 13 patients were divided into Group P and 30 in Group N. Median age at the Björk procedure was 5.7 (2.1-7.3) years, and median follow-up was 32 (28-36) years. Survival after 15 years was higher in Group P, compared with Group N (100% vs 76% at 30 years, P = .045). Cardiac catheterization data demonstrated higher cardiac index in Group P patients compared with Group N patients (3.5 vs 2.8 L/m2, P = .014). Cardiac magnetic resonance imaging study revealed that Group P patients had higher right ventricular end-diastolic volume index (96 vs 57 mL/m2, P = .005), higher end-systolic volume index (49 vs 30 mL/m2, P = .013) and higher right ventricular stroke volume index (48 vs 25 mL/m2, P < .001), compared with Group N patients. Exercise capacity tests demonstrated that Group P patients showed a higher percent predicted peak oxygen consumption, compared with Group N patients (73 vs 58%, P < .001). Conclusions: Late after the Björk procedure, patients with a pulsatile systolic pulmonary flow had a larger right ventricle and better exercise capacity compared with those without pulsatile systolic pulmonary flow.


[Role of genetic factors in the etiology of silicosis].
Examination of 15 systems of hereditary polymorphism including HLA system was conducted in 284 patients suffering from silicosis and 431 healthy subjects. The results provided genetic factors showing propensity to and resistance against silicosis. The data served as a base for silicosis risk groups formation among the staffers at occupational risk of silicosis, for occupational selection during placement to enterprises with silicosis danger.


Crohn's disease beginning during pregnancy.
I have reported the 11th case of Crohn's disease initially symptomatic during pregnancy. The complication rate is very high in this rare clinical syndrome. Of the ten previously described patients, five had surgical intervention during pregnancy. Seven of twelve infants and two of the 11 patients ultimately died. The prognosis is probably no better now than it was when the entity was initially described 40 years ago.


The landscape of human genes involved in the immune response to parasitic worms.
More than 2 billion individuals worldwide suffer from helminth infections. The highest parasite burdens occur in children and helminth infection during pregnancy is a risk factor for preterm delivery and reduced birth weight. Therefore, helminth infections can be regarded as a strong selective pressure. Here we propose that candidate susceptibility genes for parasitic worm infections can be identified by searching for SNPs that display a strong correlation with the diversity of helminth species/genera transmitted in different geographic areas. By a genome-wide search we identified 3478 variants that correlate with helminth diversity. These SNPs map to 810 distinct human genes including loci involved in regulatory T cell function and in macrophage activation, as well as leukocyte integrins and co-inhibitory molecules. Analysis of functional relationships among these genes identified complex interaction networks centred around Th2 cytokines. Finally, several genes carrying candidate targets for helminth-driven selective pressure also harbour susceptibility alleles for asthma/allergy or are involved in airway hyper-responsiveness, therefore expanding the known parallelism between these conditions and parasitic infections. Our data provide a landscape of human genes that modulate susceptibility to helminths and indicate parasitic worms as one of the major selective forces in humans.


From induced to programmed lymphoid tissues: the long road to preempt pathogens.
In mammalian fetuses, ontogeny dictates the development of secondary lymphoid tissues, the spleen, the lymph nodes and the Peyer's patches. In adults, commensals, infectious microbes and inflammation induce the formation of small reversible lymphoid tissues resembling lymph nodes or Peyer's patches. Crucial to lymphoid-tissue genesis is lymphotoxin-beta receptor-mediated activation of inflammatory effectors and structural chemokines. This pathway might have existed since the advent of the vertebrate lymphocyte system to organize local adaptive immunity in response to microbes; however, it only operates in the absence of microbes in mammals, resulting in the development of secondary lymphoid tissues and in preempting pathogens.


Detection and molecular characterization of Escherichia coli CTX-M-15 and Klebsiella pneumoniae SHV-12 β-lactamases from bovine mastitis isolates in the United Kingdom.
Recent reports raised concerns about the role that farm stock may play in the dissemination of extended-spectrum β-lactamase (ESBL)-producing bacteria. This study characterized the ESBLs in two Escherichia coli and three Klebsiella pneumoniae subsp. pneumoniae isolates from cases of clinical bovine mastitis in the United Kingdom. Bacterial culture and sensitivity testing of bovine mastitic milk samples identified Gram-negative cefpodoxime-resistant isolates, which were assessed for their ESBL phenotypes. Conjugation experiments and PCR-based replicon typing (PBRT) were used for characterization of transferable plasmids. E. coli isolates belonged to sequence type 88 (ST88; determined by multilocus sequence typing) and carried blaCTX-M-15 and blaTEM-1, while K. pneumoniae subsp. pneumoniae isolates carried blaSHV-12 and blaTEM-1. Conjugation experiments demonstrated that blaCTX-M-15 and blaTEM-1 were carried on a conjugative plasmid in E. coli, and PBRT identified this to be an IncI1 plasmid. The resistance genes were nontransferable in K. pneumoniae subsp. pneumoniae isolates. Moreover, in the E. coli isolates, an association of ISEcp1 and IS26 with blaCTX-M-15 was found where the IS26 element was inserted upstream of both ISEcp1 and the blaCTX-M promoter, a genetic arrangement highly similar to that described in some United Kingdom human isolates. We report the first cases in Europe of bovine mastitis due to E. coli CTX-M-15 and also of bovine mastitis due to K. pneumoniae subsp. pneumoniae SHV-12 β-lactamases in the United Kingdom. We also describe the genetic environment of blaCTX-M-15 and highlight the role that IncI1 plasmids may play in the spread and dissemination of ESBL genes, which have been described in both human and cattle isolates.


Immune protection against HSV-2 in B-cell-deficient mice.
The role of antibody in protection of the vaginal mucosa and sensory ganglia against HSV-2 infection was examined using HSV- immune, B-cell-deficient muMT mice. Significantly higher virus titers were detected in the vaginal mucosae of immune muMT mice compared to immune C57BL/6J mice 24 h after HSV-2 rechallenge. However, virus was rapidly cleared in immune muMT mice, and the infection was resolved with only a 2-day delay. Passive transfer of immune serum to immune muMT mice prior to rechallenge resulted in HSV-specific vaginal IgG levels comparable to those of immune C57BL/6J mice. Although transferred antibody failed to prevent reinfection of the majority of recipients, vaginal virus titers at 24 h and clearance kinetics were similar to those of immune C57BL/6J controls. Following vaginal rechallenge, HSV-2 did not spread to the sensory ganglia of immune C57BL/6J mice nor was the rechallenge virus detected in the ganglia of the majority of immune muMT mice. However, protection was severely compromised by T-cell depletion of immune C57BL/6J mice. These results suggest that HSV-specific antibody limits, but does not prevent, infection of the genital epithelia. Further, prevention of virus spread to the sensory ganglia in immune animals requires vigorous T-cell immune responses.


Sex determination. foxl3 is a germ cell-intrinsic factor involved in sperm-egg fate decision in medaka.
Sex determination is an essential step in the commitment of a germ cell to a sperm or egg. However, the intrinsic factors that determine the sexual fate of vertebrate germ cells are unknown. Here, we show that foxl3, which is expressed in germ cells but not somatic cells in the gonad, is involved in sperm-egg fate decision in medaka fish. Adult XX medaka with disrupted foxl3 developed functional sperm in the expanded germinal epithelium of a histologically functional ovary. In chimeric medaka, mutant germ cells initiated spermatogenesis in female wild-type gonad. These results indicate that a germ cell-intrinsic cue for the sperm-egg fate decision is present in medaka and that spermatogenesis can proceed in a female gonadal environment.


Apolipoprotein E genotype influences cognitive 'phenotype' in patients with Alzheimer's disease but not in healthy control subjects.
We examined the association of apolipoprotein E (apo E) genotype with cognitive performance in Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) patients and in normal subjects. One hundred fifty-seven AD patients, 35 MCI patients who developed AD during longitudinal follow-up, and 341 normal control subjects from the Mayo Clinic Alzheimer's Disease Patient Registry were studied. All participants were typed for apo E using polymerase chain reaction-based assay, epsilon 4+ and epsilon 4- groups were compared on cognitive factor scores of Verbal Comprehension, Perceptual Organization, Attention/Concentration, Learning, and Retention. Raw delayed verbal recall and visual confrontation naming scores supplemented these scores. Multivariate ANOVA was completed for cognitive scores. As expected, a main effect for diagnostic group was present across all scores. Multivariate main effects for age group and apo E genotype were also statistically significant. Subsequent within-group comparisons revealed no genotype differences for control subjects across all cognitive scores except raw delayed recall where an interaction indicated that older epsilon 4+ control subjects actually scored better than younger epsilon 4+ patients. Genotype differences were present for the Retention factor in the MCI sample and for Verbal Comprehension and Learning in the AD sample. In a combined cognitive impairment sample (AD + MCI), genotype differences were present for Verbal Comprehension, Learning, and Retention. Possession of an apo E epsilon 4 allele did not appear to be associated with poorer cognitive performance among normal control subjects. In the AD and MCI samples, epsilon 4+ status was associated with greater memory impairment in analyses including duration of illness as a covariate. In combined AD + MCI analyses, epsilon 4 homozygosity was associated with poorer retention, learning, and verbal comprehension at a given disease duration. Possession of the epsilon 4 genotype may influence cognition in a dose-response relationship.


Inversion of Fabry-Perot CCD images: use in Doppler shift measurements.
We consider how to use a charge-coupled device (CCD) as an imaging device for a Fabry-Perot interferometer. When the CCD is used in a conventional manner (pixel by pixel readout), the read noise limits its usefulness. Instead, we propose using the CCD in an operational mode so that the 2-D circular symmetric Fabry-Perot interference pattern is read as a 1-D array. The recovery of the signal is effected by carrying out an Abel inversion of the 1-D array. We show how by carrying out this operation it is possible to reduce greatly the effect of read noise. Finally, we consider how this image technique reflects on the accuracy of a Doppler shift measurement.


Epidermal growth factor receptor phosphorylation sites Ser991 and Tyr998 are implicated in the regulation of receptor endocytosis and phosphorylations at Ser1039 and Thr1041.
Aberrant expression, activation, and down-regulation of the epidermal growth factor receptor (EGFR) have causal roles in many human cancers, and post-translational modifications including phosphorylation and ubiquitination and protein-protein interactions directly modulate EGFR function. Quantitative mass spectrometric analyses including selected reaction monitoring (also known as multiple reaction monitoring) were applied to the EGFR and associated proteins. In response to epidermal growth factor (EGF) stimulation of cells, phosphorylations at EGFR Ser(991) and Tyr(998) accumulated more slowly than at receptor sites involved in RAS-ERK signaling. Phosphorylation-deficient mutant receptors S991A and Y998F activated ERK in response to EGF but were impaired for receptor endocytosis. Consistent with these results, the mutant receptors retained a network of interactions with known signaling proteins including EGF-stimulated binding to the adaptor GRB2. Compared with wild type EGFR the Y998F variant had diminished EGF-stimulated interaction with the ubiquitin E3 ligase CBL, and the S991A variant had decreased associated ubiquitin. The endocytosis-defective mutant receptors were found to have elevated phosphorylation at positions Ser(1039) and Thr(1041). These residues reside in a serine/threonine-rich region of the receptor previously implicated in p38 mitogen-activated protein kinase-dependent stress/cytokine-induced EGFR internalization and recycling (Zwang, Y., and Yarden, Y. (2006) p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy. EMBO J. 25, 4195-4206). EGF-induced phosphorylations at Ser(1039) and Thr(1041) were blocked by treatment of cells with SB-202190, a selective inhibitor of p38. These results suggest that coordinated phosphorylation of EGFR involving sites Tyr(998), Ser(991), Ser(1039), and Thr(1041) governs the trafficking of EGF receptors. This reinforces the notion that EGFR function is manifest through spatially and temporally controlled protein-protein interactions and phosphorylations.


Like/dislike analysis using EEG: determination of most discriminative channels and frequencies.
In this study, we have analyzed electroencephalography (EEG) signals to investigate the following issues, (i) which frequencies and EEG channels could be relatively better indicators of preference (like or dislike decisions) of consumer products, (ii) timing characteristic of "like" decisions during such mental processes. For this purpose, we have obtained multichannel EEG recordings from 15 subjects, during total of 16 epochs of 10 s long, while they were presented with some shoe photographs. When they liked a specific shoe, they pressed on a button and marked the time of this activity and the particular epoch was labeled as a LIKE case. No button press meant that the subject did not like the particular shoe that was displayed and corresponding epoch designated as a DISLIKE case. After preprocessing, power spectral density (PSD) of EEG data was estimated at different frequencies (4, 5, …, 40 Hz) using the Burg method, for each epoch corresponding to one shoe presentation. Each subject's data consisted of normalized PSD values (NPVs) from all LIKE and DISLIKE cases/epochs coming from all 19 EEG channels. In order to determine the most discriminative frequencies and channels, we have utilized logistic regression, where LIKE/DISLIKE status was used as a categorical (binary) response variable and corresponding NPVs were the continuously valued input variables or predictors. We observed that when all the NPVs (total of 37) are used as predictors, the regression problem was becoming ill-posed due to large number of predictors (compared to the number of samples) and high correlation among predictors. To circumvent this issue, we have divided the frequency band into low frequency (LF) 4-19 Hz and high frequency (HF) 20-40 Hz bands and analyzed the influence of the NPV in these bands separately. Then, using the p-values that indicate how significantly estimated predictor weights are different than zero, we have determined the NPVs and channels that are more influential in determining the outcome, i.e., like/dislike decision. In the LF band, 4 and 5 Hz were found to be the most discriminative frequencies (MDFs). In the HF band, none of the frequencies seemed offer significant information. When both male and female data was used, in the LF band, a frontal channel on the left (F7-A1) and a temporal channel on the right (T6-A2) were found to be the most discriminative channels (MDCs). In the HF band, MDCs were central (Cz-A1) and occipital on the left (O1-A1) channels. The results of like timings suggest that male and female behavior for this set of stimulant images were similar.


Seeking support on facebook: a content analysis of breast cancer groups.
Social network sites have been growing in popularity across broad segments of Internet users, and are a convenient means to exchange information and support. Research on their use for health-related purposes is limited. This study aimed to characterize the purpose, use, and creators of Facebook groups related to breast cancer. We searched Facebook (www.Facebook.com) using the term breast cancer. We restricted our analysis to groups that were related to breast cancer, operated in English, and were publicly available. Two of us independently extracted information on the administrator and purpose of the group, as well as the number of user-generated contributions. We developed a coding scheme to guide content analysis. We found 620 breast cancer groups on Facebook containing a total of 1,090,397 members. The groups were created for fundraising (277/620, 44.7%), awareness (236, 38.1%), product or service promotion related to fundraising or awareness (61, 9%), or patient/caregiver support (46, 7%). The awareness groups as a whole contained by far the most members (n = 957,289). The majority of groups (532, 85.8%) had 25 wall posts or fewer. The support oriented groups, 47% (27/57) of which were established by high school or college students, were associated with the greatest number of user-generated contributions. Facebook groups have become a popular tool for awareness-raising, fundraising, and support-seeking related to breast cancer attracting over one million users. Given their popularity and reach, further research is warranted to explore the implications of social network sites as a health resource across various health conditions, cultures, ages, and socioeconomic groups.


Fibronectin in cell adhesion and migration via N-glycosylation.
Directed cell migration is an important step in effective wound healing and requires the dynamic control of the formation of cell-extracellular matrix interactions. Plasma fibronectin is an extracellular matrix glycoprotein present in blood plasma that plays crucial roles in modulating cellular adhesion and migration and thereby helping to mediate all steps of wound healing. In order to seek safe sources of plasma fibronectin for its practical use in wound dressing, we isolated fibronectin from human (homo) and porcine plasma and demonstrated that both have a similar ability as a suitable substrate for the stimulation of cell adhesion and for directing cell migration. In addition, we also defined the N-glycosylation sites and N-glycans present on homo and porcine plasma fibronectin. These N-glycosylation modifications of the plasma fibronectin synergistically support the integrin-mediated signals to bring about mediating cellular adhesion and directed cell migration. This study not only determines the important function of N-glycans in both homo and porcine plasma fibronectin-mediated cell adhesion and directed cell migration, but also reveals the potential applications of porcine plasma fibronectin if it was applied as a material for clinical wound healing and tissue repair.


Differential impairment of adherens-junction expression/phosphorylation after cardioplegia in diabetic versus non-diabetic patients.
Previous animal studies have demonstrated that endothelial adherens-junction molecules are significantly altered in animal myocardium and microvasculature after cardioplegia and cardiopulmonary bypass (CP/CPB). We investigated the effects of diabetes on expression/phosphorylation/localization of vascular endothelial (VE)-cadherin, β- and γ-catenin in human atrial myocardium and coronary vasculature in the setting of CP/CPB. Right atrial tissue was harvested pre- and post-CP/CPB from non-diabetic (ND) [haemoglobin A1c (HbA1c): 5.4 ± 0.15], controlled (CDM) (HbA1c: 6.3 ± 0.14) and uncontrolled diabetic (UDM) (HbA1c: 9.9 ± 0.72) patients (n = 10/group). Expression/phosphorylation/localization of VE-cadherin, β- and γ-catenin were assessed by immunoblotting, immunoprecipitation and immunohistochemistry. In vitro atrial microvascular reactivity was assessed by videomicroscopy in response to the endothelium-dependent vasodilator adenosine 5'-diphosphate (ADP). There were no significant differences in VE-cadherin protein expression between pre- and post-CP/CPB among groups. There were significant decreases in VE-cadherin densities in vessels of the UDM group versus the ND group at baseline or post-CP/CPB, respectively (P < 0.05). The level of basal phosphorylated VE-cadherin tends to be higher in the UDM compared with the ND group (P < 0.05). CP/CPB induced more phosphorylation of VE-cadherin in all groups (versus pre-CP/CPB; P < 0.05, respectively) and this effect was more pronounced in the UDM group (P < 0.05 versus ND or CDM). The protein levels of both catenins (β and γ) were lower in post-CP/CPB in UDM than ND patients (P < 0.05). There were significant decreases in vasodilatory response to endothelial-dependent vasodilator ADP after CP/CPB (P < 0.05). This alteration was more pronounced in UDM patients (P < 0.05). These data suggest that poorly controlled diabetes down-regulates endothelial adherens-junction protein activation/expression/localization in the setting of CP/CPB. The increased tyrosine phosphorylation and deterioration of VE-cadherin indicate the damage of the cell-cell endothelial junctions in the diabetic vessels undergoing CP/CPB and cardiac surgery. These alterations may lead to increase in vascular permeability and endothelial dysfunction and affect outcomes in diabetic patients after cardiac surgery.


Psychosis in temporal lobe epilepsy: atypical presentation.
A 55-year-old lady was admitted following a concern raised by family members who had noticed a change in behaviour in terms of declining mood, paranoia with expression of belief that she was being bugged, also reported smelling perfume and after shave lotion. She had a prior diagnosis of bipolar mood disorder and was on lithium but remained no-compliant with her prescribed medication in the 10 weeks before admission. Upon admission, necessary investigations were performed including CT scan and EEG. Her CT was normal but EEG was grossly abnormal. Neurology consultation was sought and a sleep deprived EEG and MRI was ordered. Meanwhile, carbamezipine was commenced in view of the change in diagnosis to that of temporal lobe epilepsy. The patient responded very well to this regime and improved in all spheres. She was finally discharged with follow-up appointments with both neurology and psychiatry clinics.


When the security measure meets bordered penality: Release procedures for persons who are not criminally responsible without residence rights in Belgium.
Offenders considered to be persons not criminally responsible (hereafter Persons NCR) in Belgium, are subjected to a security measure. This is executed by means of a forensic care trajectory, often beginning in high-security prison units or forensic psychiatric facilities, and moving through medium and lower security psychiatric facilities, with the intention to ultimately integrate them back into society. Within this group there are 145 persons without residence rights. This article is attentive to how the forensic care trajectories for people without residence rights are currently navigated. Six qualitative interviews were conducted with key decision-makers in the forensic care trajectories of Persons NCR. Moreover, we analyse the legislative framework regarding the security measure and illustrate how features of 'bordered penality' are clearly present. Our results indicate that when working towards a return to the country of origin fails, Persons NCR without residence rights become neglected, either in high-security prison units or forensic facilities. We explore avenues to improve this precarious situation, and consider possibilities to guarantee mental healthcare according to a persons' security needs rather than their residence rights.


Cervical spine involvement early in the course of rheumatoid arthritis.
Cervical spine involvement in rheumatoid arthritis (RA) is considered a feature of long-standing disease. We describe two patients who presented with cervical symptoms as early features of RA. We report two RA cases with cervical spine involvement as early features and use MEDLINE to review the literature concerning the frequency and disease duration of this manifestation and its imaging with plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI). An 80-year-old man with cervical myelopathy from a C1-C2 rheumatoid pannus underwent decompression surgery before development of peripheral synovitis from RA. A 63-year-old woman presented with neck pain and polyarthritis at RA diagnosis, with imaging that confirmed a C1-C2 rheumatoid pannus. Onset of cervical spine involvement in RA is generally after 10 years of disease duration, ranging from 3 months to 45 years after peripheral synovitis among patients with seropositive erosive RA. Occurring in 9-88% of RA patients, cervical spine involvement may result in cervical instability due to either mechanical compression or vascular impairment of the spinal cord. Bone erosions and atlanto-axial subluxation on standard radiographs are two major signs of cervical spine involvement in RA. MRI identifies earlier signs of RA and has a higher sensitivity in detecting bone erosions compared to conventional radiography. Cervical spine involvement in RA is not an uncommon condition but is rare at early disease onset. Symptoms of cervical pain and myelopathy should prompt a thorough neurological examination accompanied by imaging.


Epileptogenic agents enhance transmission at an identified weak electrical synapse in Aplysia.
To examine the possibility that alterations in the effectiveness of electrical synapses might participate in epileptogenesis, the effects of several convulsants on an identified weak electrical synapse in Aplysia were examined. Application of pentylenetetrazole, strychnine, or tetraethylammonium led to a dramatic increase in the size of the electrical postsynaptic potential mediated by the synapse; penicillin was considerably less effective. In a number of animals, the increased electrical synaptic effectiveness led to the abnormal conduction of spikes across the synapse. If convulsants have a similar action in mammalian cortex, enhanced transmission at weak electrical synapses may provide abnormal pathways for the flow of seizure activity and contribute in part to the synchronous firing of neurons characteristic of epileptic activity.


Long-term follow-up of boys who have undergone a testicular biopsy for fertility preservation.
What is the long-term reproductive health outcome of patients who have undergone testicular sampling for fertility preservation (FP) before and during the pubertal transition period? In long-term follow-up after testicular sampling for FP, hormonal data showed that 33% of patients had primary seminiferous tubule insufficiency (high FSH) while semen analyses showed 52% of patients having a severe reduction in total sperm counts or complete absence of ejaculated sperm. During childhood and adolescence, both treatments for cancer and benign haematological diseases that require a bone marrow transplantation, can be detrimental to spermatogenesis by depleting the spermatogonial stem cell population. A testicular biopsy prior to chemotherapy or radiotherapy, even though still an experimental procedure, is now recommended for FP by European and USA oncofertility societies if performed within an institutional research setting. While short-term follow-up studies showed little to no post-operative complications and a normal testicular development after 1 year, data regarding the long-term follow-up of boys who have undergone this procedure are still lacking. This is a longitudinal retrospective cohort study that reports on the long-term follow-up of pre- and peri-pubertal boys who have undergone a testicular biopsy for FP between May 2005 and May 2020. All the patients included in this study were referred to our programme by haematologists-oncologists who are part of a regional multi-centric collaborative care pathway. Of the 151 boys referred to our FP programme, 139 parents/legal guardians accepted that their child undergo a testicular biopsy. Patient characteristics (i.e. age at biopsy, urogenital history, pubertal status at diagnosis), indications (disease type and dosage of gonadotoxic treatments), operative and post-operative data (biopsy volume, surgical complications), anatomopathological analyses (presence/absence of spermatogonia, Johnsen score) and reproductive data (semen analyses, FSH, LH, testosterone levels) were collected from the institutions' FP database and medical records or from the 'Brussels Health Network'. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Patients who were 14 years or older at the time of the follow-up and in whom the testicular tissue was shown to contain spermatogonia were included in the reproductive outcome analysis. Comparison of the sperm count findings (absence/presence of spermatozoa) and FSH levels (high (≥10 IU/l)/normal) between patients who were either pre- (Tanner 1) or peri-pubertal (Tanner >1) at the time of the biopsy was done using the Mann-Whitney U or Fisher's tests. A multiple logistic regression was used to study the relationship between the hormone reproductive outcome (high versus normal FSH), as a proxy marker for fertility, and both the pubertal status (Tanner 1 versus Tanner >1) and Johnsen score at the time of the biopsy, while adjusting for CED. A testicular biopsy was performed in 139 patients either before (129/139) or after (10/139) the start of a gonadotoxic treatment. Post-operative complications occurred in 2.1% (3/139). At the time of the procedure, 88% (122/139) of patients were pre-pubertal and 12% (17/139) were peri-pubertal. The presence of spermatogonia was documented in 92% (128/139) of cases. Follow-up data were available for 114 patients after excluding 23 deceased and two patients lost to follow-up. A paediatric endocrinologist's follow-up including clinical examination and data on reproductive hormones was available for 57 patients (age ≥14) and 19 (33%) of these were found to have high FSH levels (20 ± 8.8 IU/l). There were 37 patients who had returned to the reproductive specialist's consultation for post-treatment fertility counselling and results on semen analysis were available in 27 of these cases; 14/27 (52%) had severely impaired semen parameters including 8 who were azoospermic. Among patients who received an alkylating agent-based treatment (n = 42), a peri-pubertal status (Tanner >1) at the time of diagnosis/biopsy was found to be associated with a higher risk of having primary testicular failure (defined by an FSH ≥ 10 IU/l) after treatment completion with an OR of 6.4 (95% CI 1.22-33.9; P = 0.03). Of all the patients, 2.6% had already fulfilled their wish to build a family or were actively seeking parenthood. Although this is the largest cohort with follow-up data providing proxy markers of the reproductive potential of boys in whom a testicular biopsy for FP was performed before puberty or during the pubertal transition period, the amount of data provided is limited, and originating from a single programme. Further data collection to confirm the observations in other settings is therefore awaited. Testicular sampling for FP should be offered to boys at risk of losing their fertility (and is recommended for those at high risk) as part of ethically approved research programmes. Long-term follow-up data on increasing numbers of boys who have undergone an FP procedure will help improve patient care in the future as patient-specific factors (e.g. urogenital history, age at gonadotoxic therapy) appear to influence their reproductive potential after gonadotoxic therapies. FNRS-Télévie, the Salus Sanguinis Foundation and the Belgian Foundation against Cancer supported the studies required to launch the FP programme. The authors declare that they have no conflict of interest. N/A.


Receptive fields of motor neurons underlying local tactile reflexes in the locust.
The receptive fields of motor neurons to a hind leg were mapped by recording intracellularly from their cell bodies or from the muscle fibers they innervate while stimulating mechanoreceptors on the surface of that leg. Each motor neuron is affected by a specific array of receptors that make up its receptive field. Boundaries along the anteroposterior or dorsoventral axes of the leg divide the receptive fields into excitatory and inhibitory regions. Proximodistal boundaries may correspond to the articulations between parts of the leg. Motor neurons that innervate antagonistic muscles have complementary receptive fields, so that the region that is excitatory for one is inhibitory for the other. The receptive fields of the motor neurons overlap. Tactile stimulation therefore leads to a specific local reflex that involves the coordinated movement of the segments of a leg. Five local reflexes are described, each of which moves the leg away from the site of stimulation. Afferents from the external mechanoreceptors do not synapse directly on the motor neurons, but instead on spiking local interneurons, some of which then synapse directly on motor neurons. These local interneurons have smaller receptive fields delineated by the same boundaries, so that the receptive fields of the motor neurons can be constructed from appropriate combinations of them. It is suggested that receptive fields are organized as "functional maps" that are appropriate for particular behavioral responses rather than solely to preserve or refine spatial information.


Performance quantification of applicators for microwave treatment of crushed mineral ore.
Exposure of crushed mineral ores to microwaves at high power density (-10(9) to 10(11) W/ m3(abs)) and for short exposure times (< 0.1 s) induces grain boundary fracture around the grains of the value minerals at economically viable energy inputs (-1 kWh/t). In subsequent processing steps, liberation of the value minerals is enhanced, improving the efficiency of the process. In this paper the performance of transverse E-field applicators for the continuous treatment of 30 t/h of crushed ore was quantified using damage maps. These provide the amount of microwave-induced grain boundary damage and the fraction of the load treated as a function of input power and throughput. The damage maps are created by combining the outputs from thermal stress simulations (for the determination of thermal damage) with those from electromagnetic simulations (for the determination of the 3d dissipation of power in the load). The results are to be used to select the optimal applicator structure and operating parameters (bed height and speed) for a given ore. Results from two applicator configurations for a coarser and finer-grained galena-calcite ore are used to exemplify the results. It is shown high the texture of the ore significantly reduces performance in terms of achievable throughput and required energy input. It is also shown that sub-optimal electromagnetic design also results in reduced throughput and increased energy requirement.


Case report: psychosis with Stevens-Johnson syndrome and toxic epidermal necrolysis.
A case is presented of a 36-year-old woman who developed a psychosis following an apparent systemic allergic reaction to phenytoin and/or phenobarbital. She was initially diagnosed as having Stevens-Johnson syndrome and toxic epidermal necrolysis with the subsequent development of a psychosis. The authors were able to demonstrate a previously undiagnosed neurological impairment that they feel may be related to both the drug reaction and the psychosis.


Effects of Eriobotrya japonica seed extract on oxidative stress in rats with non-alcoholic steatohepatitis.
Non-alcoholic steatohepatitis is associated with the deposition of lipid droplets in the liver, and is characterised histologically by the infiltration of inflammatory cells, hepatocellular degeneration and liver fibrosis. Oxidative stress may play an important role in the onset and deterioration of non-alcoholic steatohepatitis. We previously reported that an Eriobotrya japonica seed extract, extracted in 70% ethanol, exhibited antioxidant actions in vitro and in vivo. In this study, we examined the effect of this extract in a rat model of non-alcoholic steatohepatitis. The seed extract was given in the drinking water to fats being fed a methionine-choline-deficient diet for 15 weeks. Increases in alanine aminotransferase and aspartate aminotransferase levels were significantly inhibited in rats fed the seed extract compared with the group on the diet alone. Formation of fatty droplets in the liver was also inhibited. Antioxidant enzyme activity in liver tissue was higher than in the diet-only group and lipid peroxidation was reduced compared with rats that also received the extract. Expression of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal was lower in the rats given the seed extract than in the diet-only group. In the former, liver tissue levels of transforming growth factor-beta and collagen were also decreased. Thus, the E. japonica seed extract inhibited fatty liver, inflammation and fibrosis, suggesting its usefulness in the treatment of non-alcoholic steatohepatitis.


The effect of glycosaminoglycans (GAGs) on amyloid aggregation and toxicity.
Amyloidosis is a protein folding disorder in which normally soluble proteins are deposited extracellularly as insoluble fibrils, impairing tissue structure and function. Charged polyelectrolytes such as glycosaminoglycans (GAGs) are frequently found associated with the proteinaceous deposits in tissues of patients affected by amyloid diseases. Experimental evidence indicate that they can play an active role in favoring amyloid fibril formation and stabilization. Binding of GAGs to amyloid fibrils occurs mainly through electrostatic interactions involving the negative polyelectrolyte charges and positively charged side chains residues of aggregating protein. Similarly to catalyst for reactions, GAGs favor aggregation, nucleation and amyloid fibril formation functioning as a structural templates for the self-assembly of highly cytotoxic oligomeric precursors, rich in β-sheets, into harmless amyloid fibrils. Moreover, the GAGs amyloid promoting activity can be facilitated through specific interactions via consensus binding sites between amyloid polypeptide and GAGs molecules. We review the effect of GAGs on amyloid deposition as well as proteins not strictly related to diseases. In addition, we consider the potential of the GAGs therapy in amyloidosis.


Serum leptin levels and body composition in postmenopausal women treated with tibolone and raloxifene.
To compare body composition and serum leptin levels in untreated postmenopausal women and postmenopausal women treated with tibolone or raloxifene. This was a prospective, randomized, controlled study. Sixty-eight postmenopausal women were randomized to receive either no treatment (group A, n = 21) or tibolone 2.5 mg/day (group B; n = 23) or raloxifene 60 mg/day (group C; n = 24). All women underwent height, weight, body mass index evaluation and dual energy x-ray absorptiometry determination of body composition at the beginning of the study and after 12 months. Serum leptin levels were determined at the beginning of the study and after 1, 3, 6, and 12 months in all groups. Women in group A showed no significant changes in both fat and lean mass of arms and legs, whereas a significant increase in trunk fat mass, total fat mass, total percentage of body fat, and trunk percentage of fat was detected 1 year after the beginning of the study. After 12 months, the total percentage of fat mass was significantly higher in group A compared with group B, and the trunk percentage of fat mass was significantly higher in group A compared with groups. In subjects in groups B and C, after 1 year, fat mass, both total and at all areas evaluated, did not show any significant change compared with baseline values. In subjects in group B, total lean and lean mass of the trunk and legs increased significantly at the end of the study, whereas no significant changes were observed in lean mass, total and at all areas evaluated in subjects in group C. After 12 months, total lean mass and lean mass of the legs were significantly higher in group B compared with the other groups. In group A, serum leptin levels were significantly increased at the end of the study compared with baseline values. Leptin concentrations were significantly higher in group A compared with groups B and C after 6 and 12 months. No significant change in serum leptin levels in subjects in groups B and C was detected throughout the study. Serum leptin levels showed a positive, significant correlation with all body composition parameters and body mass index in all groups at the beginning and at the end of the study. The present study confirms that postmenopausal hypoestrogenism leads to increased fat content and serum leptin levels. Raloxifene and tibolone seem to prevent postmenopausal body composition changes without significant modifications of serum leptin levels.


Factors Associated With Classification of Hyperplastic Polyps as Sessile Serrated Adenomas/Polyps on Morphologic Review.
Distinguishing sessile serrated adenomas/polyp (SSA/P), a subset of serrated polyps, from hyperplastic polyps (HPs) remains a challenge and has surveillance implications. Our goal was to identify clinical and pathologic factors associated with serrated polyps originally read as HPs being reassessed as SSA/Ps versus confirmed as HPs. Data were collected from consecutive patients with a right-sided HP and a corresponding comparison group with conventional adenomas between 1993 and 2003. Two experienced gastrointestinal pathologists, blinded to polyp and clinical factors, reinterpreted the HPs using current SSA/P classification criteria. These HPs were classified as SSA/P when diagnostic histologic feature(s) were present in at least 3 crypts. Analyses, conducted on a per polyp basis, examined the factors associated with risk of individual HPs being reassessed as SSA/Ps as opposed to being confirmed as HPs. Of the 702 HPs (355 adults), 188 (26.8%) were reclassified as SSA/Ps. Predictors of HPs being reinterpreted as SSA/Ps included: size ≥5 mm [odds ratio (OR), 2.09; 95% confidence interval (CI), 1.34-3.26], proximal location (OR, 2.83; 95% CI, 1.69-4.74), synchronous adenomas with advanced pathology (OR, 2.61; 95% CI, 1.22-5.55) and ≥1 synchronous HPs (other than HP being reassessed) reclassified as SSA/Ps (OR, 11.76; 95% CI, 6.75-20.49). Because HP versus SSP is not very reproducible the predictors of SSA/P that we identified, including size, location, and synchronous lesions, can offer some additional help to endoscopists when determining surveillance intervals in patients with serrated polyps. In addition, observed association between SSA/P with advanced conventional neoplasia (but not low-grade adenomas) suggests 2 distinct groups of patient predisposition, one with both advanced conventional and important serrated precursors (SSA/P) and the other largely restricted to nonadvanced conventional adenomas and HPs only. Whether the association reported here has to do with SSA/P diagnosis per se or generally larger size of SSA/P remains to be determined in future studies.


Estimation of economic weights for number of teats and sperm quality traits in pigs.
Accurate predictive modelling facilitates efficient and effective trait selection in animal breeding and can decrease costs while maximizing profits when raising economically important animals. The objective of this study was to extend a previously developed bioeconomic model and computer program to calculate the marginal economic values (MEVs) and economic weights (EWs) for direct and maternal pig traits affected by new reproductive traits, namely the number of sow functional teats (NFTs) and boar sperm quality traits (SQTs) that included sperm volume, sperm concentration, motility percentage and percentage of abnormal spermatozoa. The MEV of NFTs represented the cost differences between naturally and artificially reared piglets until weaning and the cost differences between naturally and artificially reared finished animals. The MEVs of SQTs expressed the saved costs for artificial insemination, assuming a decreased price per insemination dose when improving the SQTs. The absolute and relative EWs for the newly defined complex of traits in the breeding objectives for pig breeds involved in the Czech national three-way crossing system (Czech Large White [CLW], Czech Landrace [CL] and Pietrain [PN]) were calculated using gene flow methods. The NFT trait was included only for dam breeds, and the relative EW averaged 3.6% of the total economic importance based on the genetic standard deviations of all 19 simultaneously evaluated traits in CLW and CL breeds. The relative EWs of the four SQTs comprised 2.0% of the total economic importance of the 19 traits in the CLW and CL dam breeds and 8% of the total economic importance of the 18 traits in the PN sire breed. Therefore, inclusion of the NFTs for dam breeds and SQTs for sire breeds in the breeding goal is recommended to aid in obtaining ideal outcomes with optimal economic values.


Eavesdropping of display devices by measurement of polarized reflected light.
Display devices, or displays, such as those utilized extensively in cell phones, computer monitors, televisions, instrument panels, and electronic signs, are polarized light sources. Most displays are designed for direct viewing by human eyes, but polarization imaging of reflected light from a display can also provide valuable information. These indirect (reflected/scattered) photons, which are often not in direct field-of-view and mixed with photons from the ambient light, can be extracted to infer information about the content on the display devices. In this work, we apply Stokes algebra and Mueller calculus with the edge overlap technique to the problem of extracting indirect photons reflected/scattered from displays. Our method applies to recovering information from linearly and elliptically polarized displays that are reflected by transmissive surfaces, such as glass, and semi-diffuse opaque surfaces, such as marble tiles and wood furniture. The technique can further be improved by applying Wiener filtering.